Preparation of pharmaceutical compositions containing tetracycline, and oxytetracycline in particular, has always presented a challenge due to aqueous solubility constraints which firstly have impact upon composition stability, and secondly upon parenteral administration.
Prior art oxytetracycline compositions have exhibited relatively high viscosity at low temperatures which makes injection difficult, have shown poor stability and suffered limitations on strength of active principle. Thus, considerable research has gone into determining suitable complexing agents and more favorable co-solvents to address these shortcomings. A review of the art suggests that presence of calcium, and especially magnesium the formulation now appears mandatory as a complexing agent and whereas some improvements have been made in stability and delivery by adopting various co-solvent systems, higher concentration loadings and residual effects remain areas in which improvements are needed. This is especially of interest for veterinary purposes where the need is to deliver high effective doses with minimum effort in animal handling and detrimental effect on the animals requiring treatment.
At the current time, prior art so-called "long-acting" oxytetracycline formulations typically contain 200 mg/ml oxytetracycline and are administered at doses of about 20 mg/kg body weight, having activity as determined by residual blood levels of oxytetracycline detectable for up to about four days or so.
Solubility of oxytetracycline in non-aqueous solvents was considered by Eugene Gans and Takeru Higuchi, Journal of the American Pharmaceutical Association, 1957, Vol XLVI, pp. 587-591.
The patent literature in this area is extensive and one could refer to the following patents which are illustrative of the decades of research carried out on formulation of tetracycline compositions:
GB-A-894 619, GB-A-1 131 007, GB-A-1 250 304, PA0 GB-A-1 286 351, GB-A-1 427 882, GB-A-1 494 558, PA0 GB-A-1 508 601, GB-A-1 514 838, GB-A-1 520 197, PA0 GB-A-1 538 903, GB-A-1 563 478, GB-A-1 592 053 PA0 GB-A-2 047 097, EP-B-38 103, EP-B-96 942; U.S. Pat. No. 2,516,080, PA0 U.S. Pat. No. 2,980,584, U.S. Pat. No. 2,990,331, U.S. Pat. No. 3,062,717, PA0 U.S. Pat. No. 3,219,529, U.S. Pat. No. 3,557,280, U.S. Pat. No. 3,712,949, PA0 U.S. Pat. No. 3,957,972, U.S. Pat. No. 4,011,313, U.S. Pat. No. 4,018,889, PA0 U.S. Pat. No. 4,020,162, U.S. Pat. No. 4,126,680, U.S. Pat. No, 4,386,083, PA0 U.S. Pat. No. 4,399,127 U.S. Pat. No. 4,772,460, U.S. Pat. No. 4,957,972, and PA0 U.S. Pat. No. 5,075,295.
From these documents it is apparent that a variety of water-dispersible complex-stabilizers or water-miscible co-solvents have been proposed including 2-pyrrolidone, polyvinyl pyrrolidone, polyethylene glycols, caprolactam, 2-piperidone, and glycerol formal (a reaction product of glycerol and formaldehyde) in specific formulations. However, it is by no means clear that the said co-solvents are equally interchangeable nor can the effect of such a change be entirely predictable for a given formulation.
U.S. Pat. No. 4,386,083 proposes use of glycol formal in conjunction with magnesium acetate and magnesium chloride, whilst U.S. Pat. No. 4,772,460 proposes use of N-methylpyrrolidone (1-methyl-2-pyrrolidone) and a soluble magnesium compound. U.S. Pat. No. 5,075,295 is particularly directed to a composition aiming to achieve up to 30% oxytetracycline, which contains polyethylene glycol 400 and magnesium oxide, but examples given only appear to show a capability of achieving up to 25% oxytetracycline and there is to applicant's knowledge no current commercially available product capable of achieving greater than 20%.
An object of this invention is to provide compositions of substantially greater, long acting effect while minimizing to the greatest extent possible the defects observed in previously proposed formulations. In particular, the invention provides for administration of oxytetracycline formulations at doses ranging from 10 to 40 mg/kilogram bodyweight, giving at 30 mg/kg in animals an extended duration of plasma levels against susceptible organisms in excess of 9 days which is a surprising achievement in light of the known prior art.